Cancer-specific promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene as an important prognostic biomarker of gastric cancer

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

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Evidence of origin with epigenetic change of metachronous lesions in early gastric cancer after endoscopic submucosal dissection

10.21203/rs.3.rs-675469/v1 ◽

2021 ◽

Author(s):

Yo Kubota ◽

Satoshi Tanabe ◽

Mizutomo Azuma ◽

Kazue Horio ◽

Yoshiki Fujiyama ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Methylation ◽

Early Gastric Cancer ◽

Endoscopic Submucosal Dissection ◽

Operating Characteristic ◽

Cysteine Dioxygenase ◽

Epigenetic Change ◽

Submucosal Dissection ◽

H Pylori

Abstract Early gastric cancer (EGC) with metachronous lesions developing on scars after endoscopic submucosal dissection (ESD) is extremely rare and hard to treat. We evaluated whether DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), would predict such lesions. CDO1 methylation (TaqMeth) values were compared between 11 patients with metachronous lesions developing on scars after ESD (M group) identified from 2,055 patients (0.5%) and 33 patients with EGC with no confirmed evidence of metachronous lesions at > 3 years after ESD (solitary [S] group). To assess Helicobacter pylori influence, 11 H. pylori-negative EGC patients (N group) were also analyzed. Each ESD specimen was measured at the tumor (T) and 4-points separated tumor-adjacent noncancerous mucosa (TAM). TaqMeth values for T were significantly higher than TAM (S + M) (P = 0.0019) and TAM (N) (P < 0.0001). Moreover, TAM (M) had significantly higher TaqMeth values than TAM (S) (P < 0.0001) suggesting that TAM (M) exhibited CDO1 hypermethylation similar to T (P = 0.5713). Additionally, TaqMeth values for TAM (S) were significantly higher than TAM (N) (P < 0.0001). The receiver operating characteristic for discriminating the highest TaqMeth values separated TAMs (M) from those of TAMs (S) was 0.81. CDO1 hypermethylation promisingly predicted EGC with metachronous lesions developing on scars after ESD.

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